PROJECT SUMMARY/ABSTRACT Elevated circulating levels of fibroblast growth factor 23 (FGF23), increased serum phosphate, and anemia are associated with left ventricular hypertrophy (LVH), cardiovascular disease (CVD), and chronic kidney disease (CKD) progression in children. Current treatment strategies for CKD-mineral bone disorder and CKD-related anemia include 1,25D, binders, iron, and erythropoietin stimulating agents (ESA). However, 1,25D therapy further increases circulating and bone FGF23 levels, and iron deficiency and ESA treatment both also stimulate FGF23 production. A novel paradigm in earlier CKD has been suggested with the use of phosphate binders with or without an inhibitor of enteral phosphate absorption, when serum phosphate levels are within the normal range, to lower FGF23 and to raise endogenous 1,25D levels. However, such approach led to inconsistent results. Therapy with ferric citrate (FC), on the other hand, has been shown consistently to lower FGF23 and phosphate levels while improving indices of iron metabolism in adults with CKD stages 3-4. Furthermore, FC decreased serum phosphate levels, improved iron parameters and was well tolerated in pediatric dialysis patients. Thus, FC may have added value especially for children with pre-dialysis CKD in whom iron deficiency anemia and elevated FGF23 levels are highly prevalent. Moreover, iron deficiency is a potent driver of FGF23 production. Therefore, we hypothesize that treatment with FC will lower intact FGF23 levels during a 12-month period in a randomized, double-blinded, two -arms parallel study in 160 pediatric patients with CKD stages 3-4 and normal serum phosphate levels. The multi-site trial will pursue the following specific aims: Specific Aim 1: To determine the efficacy of FC to lower serum intact FGF23 levels (primary endpoint) in pediatric patients with CKD 3?4 over 12 months. Specific Aim 2: To determine the effects of the interventions on anemia, kidney function, and indices of bone and mineral metabolism (secondary end-points). Additionally, we will perform pre- and post-treatment bone biopsies to assess bone histomorphometry and FGF23 expression in a sub-cohort of 24 UCLA patients. Specific Aim 3: To determine the safety and tolerability of FC in pediatric CKD 3-4 patients. If our hypothesis is confirmed, then a new treatment paradigm would emerge in which therapy with FC will be initiated early in CKD, when patients are normophosphatemic, slowing progressive increases in FGF23 and blunting FGF23-associated adverse renal and CVD.